The p38 mitogen-activated protein kinases are activated in response to
environmental stress and cytokines and play a significant role in
transcriptional regulation and inflammatory responses. Of the four p38 isoforms
known to date, two (p38alpha and p38beta) have been identified as targets for
cytokine-suppressive anti-inflammatory drugs. Recently, it was reported that
specific inhibition of the p38alpha isoform is necessary and sufficient for
anti-inflammatory efficacy in vivo, while further inhibition of p38beta may not
provide any additional benefit. In order to aid the development of
p38alpha-selective compounds, the three-dimensional structure of p38beta was
determined. To do so, the C162S and C119S,C162S mutants of human MAP kinase
p38beta were cloned, expressed in Escherichia coli and purified. Initial
screening hits in crystallization trials in the presence of an inhibitor led
upon optimization to crystals that diffracted to 2.05 A resolution and allowed
structure determination (PDB codes 3gc8 and 3gc9 for the single and double
mutant, respectively). The structure of the p38alpha C162S mutant in complex
with the same inhibitor is also reported (PDB code 3gc7). A comparison between
the structures of the two kinases showed that they are highly similar overall
but that there are differences in the relative orientation of the N- and
C-terminal domains that causes a reduction in the size of the ATP-binding pocket
in p38beta. This difference in size between the two pockets could be exploited
in order to achieve selectivity.

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